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Spiro derivatives and adhesion molecule inhibitors comprising the same as active ingredient

a technology of adhesion molecule and active ingredient, which is applied in the direction of peptides, drug compositions, immunological disorders, etc., can solve the problems of achieve the effect of suppressing the activation of leukocytes and not inhibiting the progress of inflammation

Inactive Publication Date: 2006-10-26
TORAY IND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] An object of the present invention is to discover a compound which inhibits cell infiltration via adhesion molecules, especially, adhesion molecule VLA-4, thereby making it possible to prevent and treat inflammatory diseases caused by infiltration of leukocytes such as monocytes, lymphocytes and eosinophils.
[0071] According to the present invention, a novel substance is provided which inhibits cell infiltration via adhesion molecules, especially, adhesion molecule VLA-4, thereby making it possible to prevent and treat inflammatory diseases caused by infiltration of leukocytes such as monocytes, lymphocytes and eosinophils.

Problems solved by technology

Since these drugs do not have an effect to suppress the process of accumulation of leukocytes to the inflammatory site as their main action, they cannot inhibit progress of inflammation.

Method used

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  • Spiro derivatives and adhesion molecule inhibitors comprising the same as active ingredient
  • Spiro derivatives and adhesion molecule inhibitors comprising the same as active ingredient
  • Spiro derivatives and adhesion molecule inhibitors comprising the same as active ingredient

Examples

Experimental program
Comparison scheme
Effect test

example 1

Methyl 2-((t-butoxy)carbonylamino)-3-((2,4,8-triaza-2-methyl-1-oxo-4-phenylspiro[4.5]dec-8-yl)carbonylamino)propanoate (1)

[0237]

[0238] Under argon atmosphere, 12.9 g of methyl 3-amino-2-((t-butoxy)carbonylamino)propanoate was dissolved in 700 ml of dichloromethane, and then 7.9 g of saturated sodium hydrogen carbonate and 14.3 g of p-nitrophenyl chloroformate were added thereto at 0° C., followed by stirring the resulting mixture at room temperature for 5.5 hours. To the reaction mixture, 21.7 g of 2,4,8-triaza-2-methyl-4-phenylspiro[4.5]decane-1-one and 41.1 ml of triethylamine were added, and the resulting mixture was stirred at room temperature for 13 hours. After concentrating the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layers were combined, washed with 0.1 N hydrochloric acid and with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue ...

example 2

Methyl 2-((t-butoxy)carbonylamino)-3-((2,4,8-triaza-1-oxo-4-phenylspiro[4.5]dec-8-yl)carbonylamino)propanoate (2)

[0241]

[0242] Under argon atmosphere, 564 mg of 1,1-carbonyldiimidazole was dissolved in 8 ml of tetrahydrofuran, and into this solution 10 ml of tetrahydrofuran containing 760 mg of methyl 3-amino-2-((t-butoxy)carbonylamino)propanoate was dropped at 0° C. over 25 minutes. The resulting solution was then stirred for 0.5 hours. To the reaction mixture, 805 mg of 2,4,8-triaza-4-phenylspiro[4.5]decane-1-one was added, and the resulting mixture was stirred at room temperature for 13 hours. To the reaction mixture, 10% aqueous citric acid was added, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with 0.1 N hydrochloric acid and with saturated saline, dried over anhydrous sodium sulfate and concentrated to obtain 1.55 g of methyl 2-((t-butoxy)carbonylamino)-3-((2,4,8-triaza-1-oxo-4-phenylspiro[4.5]dec-8-yl)carbonylamino)prop...

example 3

Methyl 2-((phenylsulfonyl)amino)-3-((2,4,8-triaza-2-methyl-1-oxo-4-phenylspiro[4.5]dec-8-yl)carbonylamino)propanoate (3)

[0245]

[0246] In 2 ml of dichloromethane, 362 mg of methyl 2-((t-butoxy)carbonylamino)-3-((2,4,8-triaza-2-methyl-1-oxo-4-phenylspiro[4.5]dec-8-yl)carbonylamino) propanoate was dissolved, and 1 ml of trifluoroacetic acid was added thereto, followed by stirring the resulting mixture at room temperature for 12 hours. The reaction mixture was concentrated then dissolved in chloroform, washed with aqueous potassium carbonate (0.5 M) and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in 4 ml of dichloromethane, and then 205 μl of triethylamine and 95 μl of benzenesulfonyl chloride were added thereto, followed by stirring the resulting mixture at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform....

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Abstract

Disclosed is the use of an adhesion molecule inhibitor that is effective in the prevention and treatment of inflammatory diseases caused by infiltration of leukocytes such as monocytes, lymphocytes and eosindphils, by inhibiting cell infiltration which mediates adhesion molecules, especially adhesion molecule VLA-4. Since the spiro acid derivatives according to the present invention are excellent in the effect of inhibiting cell adhesion via adhesion molecules, especially adhesion molecule VLA-4, they are useful as therapeutic drugs against various inflammatory diseases. For example, provided are the spiro derivative and the adhesion molecule inhibitor which includes as an active ingredient the spiro derivative as shown by the below formula (18).

Description

TECHNICAL FIELD [0001] The present invention relates to a novel spiro derivative or a pharmaceutically acceptable salt thereof, useful as an adhesion molecule inhibitor, especially VLA-4 inhibitor, to an adhesion molecule inhibitor, especially VLA-4 inhibitor, containing the same as an active ingredient, and to a therapeutic agent against inflammatory diseases containing the same as an active ingredient. BACKGROUND ART [0002] Adhesion molecules are involved in adhesion between cells and between cells and intercellular matrix and migration and activation of cells. Adhesion molecules include a number of families such as integrin family and immunoglobulin superfamily. The adhesion molecules belonging to the integrin family are those expressed on leukocytes such as lymphocytes, monocytes, basophils and eosinophils. These adhesion molecules have a heterodimer structure, in which an a chain and a β chain are non-covalently bound, and are classified into several subfamilies depending on th...

Claims

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Application Information

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IPC IPC(8): A61K31/4747C07D498/10A61P1/04A61P11/02A61P11/06A61P13/12A61P17/00A61P19/02A61P25/00A61P29/00A61P37/02A61P37/08A61P43/00C07D471/10C07K5/078
CPCA61P1/04A61P1/16A61P9/08A61P9/10A61P11/02A61P11/06A61P13/12A61P17/00A61P19/02A61P25/00A61P29/00A61P37/02A61P37/06A61P37/08A61P43/00C07D471/10C07K5/06139
Inventor ISHIGAKI, TAKESHITANIGUCHI, KOJITANIGUCHI, AKIKAINOH, MIEMEGURO, HIROYUKIISHIZAKA, YOKO
Owner TORAY IND INC
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